Ultraviolet (UV) light is a complete carcinogen that can induce skin cancer. Among many effects, UV irradiation rapidly induces activation of the c-Jun NH2-terminal protein kinase (JNK) in mammalian cells and causes cell apoptosis. However, the molecular mechanism for JNK activation by UV exposure is poorly understood. We have found that the multisubstrate adapter Gab1 plays an essential role in the signaling cascade that is upregulated by UV irradiation. Gab1-deficient fibroblast cells are defective in the induction of JNK activity by UV light, and this defect is rescued by re-introduction of Gab1. We have also found that Gab1 is constitutively associated with JNK, and that UV irradiation of cells induces tyrosine phosphorylation of Gab 1. Although preliminary data suggest a possible role for the hepatocyte growth factor (HGF) receptor c-Met, the upstream kinase(s) that phosphorylates Gab 1 in response to UV remains to be unequivocally identified. We hypothesize that Gab1, a scaffold protein without catalytic activity, orchestrates a unique combination of enzymes and signaling proteins in the cellular responses to UV exposure, which represents a novel and unexplored signaling pathway. We will take a multidisciplinary approach to elucidate the molecular mechanism for Gab 1 activity in cellular responses to UV exposure. Our specific aims are: 1) to define the signaling events upstream of Gab1 in UV-irradiated cells; 2) to dissect the biochemical machinery linking Gabl with JNK; 3) to examine the role of Gab1 in the cellular responses to UV light; and 4) to determine the role of Gab1 in the development of UV-induced skin cancer in mice. The long term goal of this work is to identify targets for pharmaceutical intervention to block pathological processes elicited by UV light.